TGF beta-activated kinase 1 (Tak1) is a serine-theonine kinase encoded by the MAP3K7 gene. Tak1, a member of the MAP kinase family, was originally identified as a downstream target of non-canonical (non-Smad) TGF-? signaling, but is now known to be a central signaling molecule for a number of intracellular signal transduction pathways, including the interleukin 1, TNF, Toll, and Wnt/?-catenin pathways. As such it is considered an important regulatory molecule that integrates multiple pathways involved in growth and differentiation. Little is known about the role of Tak1 in the normal prostate or in prostate cancer. We recently demonstrated deletion of the Tak1 locus in approximately 38% of primary prostate tumors. The prevalence of Tak1 deletion was equivalent to the prevalence of PTEN deletions in the same study population. There was significant association between loss of Tak1 and high Gleason score. Preliminary data support a role for loss of Tak1 in prostate tumorigenesis. Because of these preliminary data and the known role of Tak1 as a key integrator of multiple signals from the microenvironment, we propose the hypothesis that Tak 1 is a tumor suppresser for prostate cancer and that Tak1 functions to regulate growth and or differentiation of prostate epithelial cells in response to the microenvironment. We will test this hypothesis with a multidisciplinary approach that combines high throughput genetics with cell biology and animal model studies. Three aims are proposed. Aim 1) Association of Tak1 deletion with Gleason Grade; Aim 2) Prostate-Specific Deletion of Tak1 In Vivo; Aim 3) The role of the tumor microenvironment in Tak1 deficiency. If our hypothesis is correct these studies are significant because they will: 1) Determine the association of Tak1 deletion with prostate tumor progression prognostic markers 2) Identify Tak1 as a prostate tumor suppressor 3) Determine the role of Tak1 in the context of the tumor microenvironment. Identification of the role of Tak1 in prostate tumorigenesis and potential gene-gene interactions are also important because they may lead to novel strategies for prostate cancer therapeutic targeting. PUBLIC HEALTH RELEVANCE: Prostate cancer is a deadly disease that affects one in six men in the US. We have identified a potential prostate cancer tumor suppressor gene located on chromosome 6q15, the MAP3K7 gene. Our studies will test if this gene is a prostate cancer tumor suppressor and interrogate its downstream targets.